Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases playing key roles both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual specificity enzymes with a lipid kinase activity capable of phosphorylating phosphoinositides at the 3-hydroxyl and with a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P act as second messengers for a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking (1,2).
The mammalian PI3Ks can be divided into three classes based on their structure and substrate specificity (2). The class I PI3Ks are receptor-regulated heterodimeric enzymes that preferentially phosphorylate PtdIns(4,5)P2 in vivo. The class IA PI3Ks (consisting of p110α, p110β, or p110δ catalytic subunits) associate with an 85 kDa adaptor that is essential for interaction of these PI3Ks with receptor tyrosine kinases. The class IB PI3K (PI3Kγ) is activated by heterotrimeric G protein subunits and associates with a p101 adaptor that is important for full responsiveness to Gβγ heterodimers (3,4). Class I PI3Ks are also activated by Ras. Class II PI3 Ks are distinguished by a C-terminal C2 domain and preferentially use PtdIns and PtdIns(4)P as substrates. Class III enzymes phosphorylate only Ptdlns and lack the Ras-binding domain.